Key result
Higher AF polygenic risk score is linked to ~33% lower all-cause mortality.
Why the study?
Polygenic risk scores for AF predict incident disease, but their relevance for delineating distinct biological phenotypes and prognostic trajectories after an AF diagnosis was unclear.
Does a higher atrial fibrillation polygenic risk score (AF PRS) delineate distinct biological phenotypes and prognostic trajectories (mortality and MACE) compared to a lower AF PRS in individuals with established atrial fibrillation?
Cohort (n=27,318)
Yes
Does a higher atrial fibrillation polygenic risk score (AF PRS) delineate distinct biological phenotypes and prognostic trajectories (mortality and MACE) compared to a lower AF PRS in individuals with established atrial fibrillation?
In patients with established atrial fibrillation, polygenic risk scores differentiate atrial-predominant phenotypes (characterized by biatrial enlargement but lower mortality and MACE) from cardiometabolic-predominant phenotypes (characterized by higher comorbidity burden and worse clinical outcomes).
Higher AF polygenic risk was associated with lower mortality in established AF; hypothesis-generating for phenotype-specific prognosis and requires prospective validation.
Background Polygenic risk scores (PRS) for atrial fibrillation (AF) predict incident disease, but their relevance after AF diagnosis is unclear. We investigated whether AF PRS delineates distinct biological phenotypes and prognostic trajectories among individuals with established AF. Methods We analyzed 27,318 UK Biobank participants with AF. Standardized AF PRS and cardiometabolic trait PRS were obtained from the UK Biobank precomputed PRS resource. AF PRS was evaluated continuously and across quintiles. Associations with cross-trait PRS, comorbidities, and outcomes were assessed using multivariable regression and Cox models adjusted for age, sex, comorbidities, and oral anticoagulant use. In a cardiac magnetic resonance (CMR) subset (n = 1,548), associations between AF PRS and atrial and ventricular structure were tested. Results The highest AF PRS quintile (Q5) included 5,255 participants (mean 1.86 ± 0.48), and the lowest quintile (Q1) included 5,254 participants (–0.79 ± 0.42). Across AF PRS quintiles, lower AF genetic susceptibility was accompanied by higher cardiometabolic genetic burden, including hypertension PRS (ΔQ1–Q5 = +0.38; β = 0.0896, 95% CI 0.0811–0.0981), composite cardiovascular disease PRS (Δ = +0.35; β = 0.0826, 95% CI 0.0740–0.0911), coronary artery disease PRS, body mass index PRS, and diabetes PRS (all p < 0.001). Cardiometabolic comorbidities were more prevalent in Q1 versus Q5, including heart failure, hypertension, diabetes, obesity and chronic kidney disease (all p < 0.05). Higher AF PRS was associated with lower all-cause mortality (Q5 vs Q1 HR 0.67, 95% CI 0.62–0.73), cardiovascular death (HR 0.72, 0.65–0.80), and MACE (HR 0.79, 0.74–0.85; all p < 0.001). In CMR, higher AF PRS was linked to biatrial enlargement and reduced atrial function (LAVI β 1.56; LAEF β –1.95) alongside less ventricular remodeling (LVMI β –0.62; LVEDVI β –1.38). Conclusions In conclusion, within established AF cases, PRS delineates atrial- from cardiometabolic-predominant trajectories with distinct structural and prognostic profiles, supporting biologically informed risk stratification beyond traditional incident-risk prediction.
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Ghanbari et al. (2026) conducted a cohort in Atrial fibrillation (n=27,318). Highest atrial fibrillation polygenic risk score quintile (Q5) vs. Lowest atrial fibrillation polygenic risk score quintile (Q1) was evaluated on All-cause mortality (HR 0.67, 95% CI 0.62-0.73, p=<0.001). Higher atrial fibrillation polygenic risk score (Q5 vs Q1) was associated with lower all-cause mortality (HR 0.67; 95% CI 0.62-0.73; p<0.001) and MACE (HR 0.79; 95% CI 0.74-0.85).
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